THALASSEMIA SYNDROMES The thalassemia syndromes are inherited disorders of - or -globin biosynthesis.

s. The reduced supply of globin diminishes production of hemoglobin tetramers, causing hypochromia and microcytosis. Unbalanced accumulation of and subunits occurs because the synthesis of the unaffected globins proceeds at normal rate. Unbalanced chain accumulation dominates the clinical phenotype. Clinical severity varies widely, depending on the degree to which the synthesis of the affected globin is impaired, altered synthesis of other globin chains, and coinheritance of other abnormal globin alleles. -THALASSEMIA SYNDROMES Mutations causing thalassemia can affect any step in the pathway of globin gene expression: transcription, processing of the mRNA precursor, translation, and posttranslational metabolism of the -globin polypeptide chain. The most common forms arise from mutations that derange splicing of the mRNA precursor or prematurely terminate translation of the mRNA. Hypochromia and microcytosis due to reduced amounts of hemoglobin tetramers characterize all forms of thalassemia. In heterozygotes ( -thalassemia trait), this is the only abnormality seen; anemia is minimal. In homozygous states, unbalanced - and -globin accumulation causes accumulation of highly insoluble unpaired chains, which form toxic inclusion bodies that kill developing erythroblasts in the marrow. Few of the proerythroblasts beginning erythroid maturation survive. The few surviving red cells bear a burden of inclusion bodies, detected in the spleen, shortening the red cell life span and producing severe hemolytic anemia. The resulting profound anemia stimulates erythropoietin release and compensatory erythroid hyperplasia, but the marrow response is sabotaged by ineffective erythropoiesis. Anemia persists. Erythroid hyperplasia can become exuberant and produce extramedullary erythropoietic tissue in the liver and spleen. Massive bone marrow expansion deranges growth and development. Children develop characteristic "chipmunk" facies due to maxillary marrow hyperplasia and frontal bossing, thinning and pathologic fracture of long bones and vertebrae due to cortical invasion by erythroid elements, and profound growth retardation. Hemolytic anemia causes hepatosplenomegaly, leg ulcers, gallstones, and high-output congestive heart failure. The conscription of caloric resources to support erythropoiesis leads to inanition, susceptibility to infection, endocrine dysfunction, and, in the most severe cases, death during the first decade of life. Chronic transfusions with red cells improves oxygen delivery, suppresses the excessive ineffective erythropoiesis, and prolongs life, but the inevitable side effects, notably iron overload, usually prove fatal by age 30. Bone marrow transplantation in childhood is the only curative therapy. Severity is highly variable. Known modulating factors are those that ameliorate the burden of unpaired -globin inclusions. Alleles associated with milder synthetic defects and coinheritance of -thalassemia trait reduce clinical severity by reducing accumulation of excess globin. HbF persists to various degrees in thalassemias. -Globin gene chains can substitute for chains, simultaneously generating more hemoglobin and reducing the burden of -globin inclusions. The terms -thalassemia major and thalassemia intermedia are used to reflect the clinical heterogeneity. Patients with -thalassemia major require intensive transfusion support to survive. Patients with -thalassemia intermedia have a somewhat milder phenotype and can survive without transfusion. The terms -thalassemia minor and -thalassemia trait describe asymptomatic heterozygotes for thalassemia. -THALASSEMIA SYNDROMES The four classic thalassemias, most common in Asians, are -thalassemia-2 trait, in which one of the four -globin loci is deleted; -thalassemia-1 trait, with two deleted loci; HbH disease, with three loci deleted; and hydrops fetalis with Hb Bart's, with all four loci deleted (Table 106-4). Nondeletion forms of thalassemia also exist.

-Thalassemia-2 trait is an asymptomatic, silent carrier state. -Thalassemia-1 trait resembles -thalassemia minor. Offspring doubly heterozygous for -thalassemia-2 and -thalassemia-1 exhibit a more severe phenotype, called HbH disease. Heterozygosity for a deletion that removes both genes from the same chromosome (cis deletion) is common in Asians and Mediterranean individuals, as is homozygosity for -thalassemia-2 (trans deletion). Both produce asymptomatic hypochromia and microcytosis.
In HbH disease, HbA production is only 25 to 30% of normal. Fetuses accumulate some unpaired chains. In adults, unpaired chains accumulate and are soluble enough to form 4 tetramers called HbH. HbH forms few inclusions in erythroblasts but does precipitate in circulating red cells. Patients with HbH disease have thalassemia intermedia characterized by moderately severe hemolytic anemia but milder ineffective erythropoiesis. Survival into midadult life without transfusions is common. The homozygous state for the -thalassemia-1 cis deletion (hydrops fetalis) causes total absence of -globin synthesis. No physiologically useful hemoglobin is produced beyond the embryonic stage. Excess globin forms tetramers called Hb Bart's ( 4), which has an extraordinarily high oxygen affinity. It delivers almost no O2 to fetal tissues, causing tissue asphyxia, edema (hydrops fetalis), congestive heart failure, and death in utero. -Thalassemia-2 trait is common (15 to 20%) among people of African descent. The cis -thalassemia-1 deletion is almost never seen, however. Thus, -thalassemia-2 and the trans form of -thalassemia-1 are very common, but HbH disease and hydrops fetalis are almost never encountered. DIAGNOSIS AND MANAGEMENT The diagnosis of -thalassemia major is readily made during childhood on the basis of severe anemia accompanied by hepatosplenomegaly; profound microcytosis; a characteristic blood smear (Plate V-2); and elevated levels of HbF, HbA2, or both. Many patients require chronic hypertransfusion therapy designed to maintain a hematocrit of at least 27 to 30% so that erythropoiesis is suppressed. Splenectomy is required if the annual transfusion requirement (volume of RBCs per kilogram body weight per year) increases by >50%. Folic acid supplements may be useful. Vaccination with pneumococcal vaccine in anticipation of eventual splenectomy is advised, as is close monitoring for infection, leg ulcers, and biliary tract disease. Early endocrine evaluation is required

for glucose intolerance, thyroid dysfunction, and delayed onset of puberty or secondary sexual characteristics. Many patients develop endocrine deficiencies as a result of iron overload. Patients with -thalassemia intermedia exhibit similar stigmata but can survive without chronic hypertransfusion. Management is particularly challenging because a number of factors can aggravate the anemia, including infection, onset of puberty, and development of splenomegaly and hypersplenism. Some patients may eventually benefit from splenectomy. The expanded erythron can cause excess absorption of dietary iron and hemosiderosis, even without transfusion. -Thalassemia minor (i.e., thalassemia trait) usually presents as profound microcytosis and hypochromia with target cells but only minimal or mild anemia. The mean corpuscular volume is rarely >75 fL; the hematocrit is rarely <30 to 33%. Hemoglobin electrophoresis classically reveals an elevated HbA2 (3.5 to 7.5%), but some forms are associated with normal HbA2 and/or elevated HbF. Genetic counseling and patient education are essential. Patients with -thalassemia trait should be warned that their blood picture resembles iron deficiency and can be misdiagnosed. They should eschew routine use of iron but know that iron deficiency requiring supplementation can develop, as in other persons, during pregnancy or from chronic bleeding. Persons with -thalassemia trait may exhibit mild hypochromia and microcytosis, usually without anemia. HbA2 and HbF levels are normal. Affected individuals usually require only genetic counseling. HbH disease resembles -thalassemia intermedia, with the added complication that the HbH molecule behaves like a moderately unstable hemoglobin. Patients with HbH disease should undergo splenectomy if excessive anemia or a transfusion requirement develops. Oxidative drugs should be avoided. Iron overload leading to death can occur in more severely affected patients.

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